Method of forming an aerosol for inhalation delivery

ABSTRACT

The present invention relates to the inhalation delivery of aerosols containing small particles. Specifically, it relates to a method of forming an aerosol for use in inhalation therapy. In a method aspect of the present invention, a method of forming an aerosol for use in inhalation therapy is provided. The method involves the following steps: (a) heating a substrate coated with a composition comprising a drug at a rate greater than 1000° C./s, thereby forming an vapor; and, (b) allowing the vapor to cool, thereby forming an aerosol, which is used in inhalation therapy. In another method aspect of the present invention, a method of forming an aerosol for use in inhalation therapy is provided. The method involves the following steps: (a) heating a substrate coated with a composition comprising a drug to form a vapor, wherein the coated composition is in the form of a film less than 10μ thick; and, (b) allowing the vapor to cool, thereby forming an aerosol, which is used in inhalation therapy. In another method aspect of the present invention, a method of forming an aerosol for use in inhalation therapy is provided. The method involves the following steps: (a) heating a substrate coated with a composition comprising a drug to form a vapor in less than 100 milliseconds, wherein the vapor has a mass greater than 0.1 mg; and, (b) allowing the vapor to cool, thereby forming an aerosol, which is used in inhalation therapy.

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 10/057,198 entitled “Method and Device forDelivering a Physiologically Active Compound,” filed Oct. 26, 2001,Lloyd et al. and of U.S. patent application Ser. No. 10/057,197 entitled“Aerosol Generating Device and Method,” filed Oct. 26, 2001, Wensley etal., both of which are hereby incorporated by reference for allpurposes. This application further claims priority to U.S. provisionalapplication Ser. No. 60/296,225 entitled “Aerosol Generating Device andMethod,” filed Jun. 5, 2001, Wensley et al., the entire disclosure ofwhich is hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to the inhalation delivery ofaerosols containing small particles. Specifically, it relates to amethod of forming an aerosol for use in inhalation therapy.

BACKGROUND OF THE INVENTION

[0003] Currently, there are a number of approved devices for theinhalation delivery of drugs, including dry powder inhalers, nebulizers,and pressurized metered dose inhalers. The aerosols produced by thedevices, however, typically contain an excipient.

[0004] It is desirable to provide a method that can produce aerosols inthe absence of excipients. The provision of such a device is an objectof the present invention.

SUMMARY OF THE INVENTION

[0005] The present invention relates to the inhalation delivery ofaerosols containing small particles. Specifically, it relates to amethod of forming an aerosol for use in inhalation therapy.

[0006] In a method aspect of the present invention, a method of formingan aerosol for use in inhalation therapy is provided. The methodinvolves the following steps: (a) heating a substrate coated with acomposition comprising a drug at a rate greater than 1000° C./s, therebyforming an vapor; and, (b) allowing the vapor to cool, thereby formingan aerosol, which is used in inhalation therapy. Preferably, thesubstrate is heated at a rate greater than 2,000° C./s, 5,000° C./s,7,500° C./s, or 10,000° C./s.

[0007] In certain cases, the substrate is heated at a rate of about2,000° C./s.

[0008] Typically, the composition is coated on the substrate as a filmthat is less than 10μ thick. Preferably, the film thickness is less than5μ, 4μ, 3μ, 2μ, or 1μ thick.

[0009] Typically, the composition is coated on the substrate as a filmthat is between 10μ and 10 nm in thickness. Preferably, the filmthickness is between 5μ and 10 nm, 4μ and 10 nm, 3μ and 10 nm, 2μ and 10nm, or 1μ and 10 nm in thickness.

[0010] Typically, greater than 0.1 mg of the composition is vaporized inless than 100 milliseconds from the start of heating. Preferably, 0.25mg, 0.5 mg, 0.75 mg, or 1 mg of the composition is vaporized in lessthan 100 milliseconds from the start of heating. More preferably, thesame amount of composition list above is vaporized in less than 75milliseconds, 50 milliseconds, 25 milliseconds, or 10 milliseconds fromthe start of heating.

[0011] Typically, the formed aerosol is greater than 10 percent byweight of the drug. Preferably, it is greater than 20 percent by weightof the drug. More preferably, it is greater than 30 percent, 40 percent,50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percentor 97 percent by weight of the drug.

[0012] Typically, the formed aerosol contains less than 10 percent byweight of drug decomposition products. Preferably, it contains less than5 percent by weight of drug decomposition products. More preferably, itcontains less than 3 percent, 2 percent or 1 percent by weight of drugdecomposition products.

[0013] Typically, the drug has a decomposition index less than 0.15.Preferably, the drug has a decomposition index less than 0.10. Morepreferably, the drug has a decomposition index less than 0.05.

[0014] Typically, the drug of the composition is of one of the followingclasses: antibiotics, anticonvulsants, antidepressants, antiemetics,antihistamines, antiparkisonian drugs, antipsychotics, anxiolytics,drugs for erectile dysfunction, drugs for migraine headaches, drugs forthe treatment of alcoholism, drugs for the treatment of addiction,muscle relaxants, nonsteroidal anti-inflammatories, opioids, otheranalgesics and stimulants.

[0015] Typically, where the drug is an antibiotic, it is selected fromone of the following compounds: cefinetazole; cefazolin; cephalexin;cefoxitin; cephacetrile; cephaloglycin; cephaloridine; cephalosporins,such as cephalosporin C; cephalotin; cephamycins, such as cephamycin A,cephamycin B, and cephamycin C; cepharin; cephradine; ampicillin;amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin;amylpenicillin; azidocillin; benzylpenicillin; clometocillin;cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin;penicillins, such as penicillin N, penicillin O, penicillin S,penicillin V; chlorobutin penicillin; dicloxacillin; diphenicillin;heptylpenicillin; and metampicillin.

[0016] Typically, where the drug is an anticonvulsant, it is selectedfrom one of the following compounds: gabapentin, tiagabine, andvigabatrin.

[0017] Typically, where the drug is an antidepressant, it is selectedfrom one of the following compounds: amitriptyline, amoxapine,benmoxine, butriptyline, clomipramine, desipramine, dosulepin, doxepin,imipramine, kitanserin, lofepramine, medifoxamine, mianserin,maprotoline, mirtazapine, nortriptyline, protriptyline, trimipramine,viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine,milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine,acetaphenazine, binedaline, brofaromine, cericlamine, clovoxamine,iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine,selegiline, sibutramine, tranylcypromine, ademetionine, adrafinil,amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone,gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone,nomifensine, ritanserin, roxindole, S-adenosylmethionine, tofenacin,trazodone, tryptophan, venlafaxine, and zalospirone.

[0018] Typically, where the drug is an antiemetic, it is selected fromone of the following compounds: alizapride, azasetron, benzquinamide,bromopride, buclizine, chlorpromazine, cinnarizine, clebopride,cyclizine, diphenhydramine, diphenidol, dolasetron methanesulfonate,droperidol, granisetron, hyoscine, lorazepam, metoclopramide,metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine,scopolamine, triethylperazine, trifluoperazine, triflupromazine,trimethobenzamide, tropisetron, domeridone, and palonosetron.

[0019] Typically, where the drug is an antihistamine, it is selectedfrom one of the following compounds: azatadine, brompheniramine,chlorpheniramine, clemastine, cyproheptadine, dexmedetomidine,diphenhydramine, doxylamine, hydroxyzine, cetrizine, fexofenadine,loratidine, and promethazine.

[0020] Typically, where the drug is an antiparkisonian drug, it isselected one of the following compounds: amantadine, baclofen,biperiden, benztropine, orphenadrine, procyclidine, trihexyphenidyl,levodopa, carbidopa, selegiline, deprenyl, andropinirole, apomorphine,benserazide, bromocriptine, budipine, cabergoline, dihydroergokryptine,eliprodil, eptastigmine, ergoline pramipexole, galanthamine, lazabemide,lisuride, mazindol, memantine, mofegiline, pergolike, pramipexole,propentofylline, rasagiline, remacemide, spheramine, terguride,entacapone, and tolcapone.

[0021] Typically, where the drug is an antipsychotic, it is selectedfrom one of the following compounds: acetophenazine, alizapride,amperozide, benperidol, benzquinamide, bromperidol, buramate,butaperazine, carphenazine, carpipramine, chlorpromazine,chlorprothixene, clocapramine, clomacran, clopenthixol, clospirazine,clothiapine, cyamemazine, droperidol, flupenthixol, fluphenazine,fluspirilene, haloperidol, mesoridazine, metofenazate, molindrone,penfluridol, pericyazine, perphenazine, pimozide, pipamerone,piperacetazine, pipotiazine, prochlorperazine, promazine, remoxipride,sertindole, spiperone, sulpiride, thioridazine, thiothixene,trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine,zuclopenthixol, amisulpride, butaclamol, clozapine, melperone,olanzapine, quetiapine, and risperidone.

[0022] Typically, where the drug is an anxiolytic, it is selected fromone of the following compounds: mecloqualone, medetomidine, metomidate,adinazolam, chlordiazepoxide, clobenzepam,,flurazepam, lorazepam,loprazolam, midazolam, alpidem, alseroxlon, amphenidone, azacyclonol,bromisovalum, buspirone, calcium N-carboamoylaspartate, captodiamine,capuride, carbcloral, carbromal, chloral betaine, enciprazine,flesinoxan, ipsapiraone, lesopitron, loxapine, methaqualone, methprylon,propanolol, tandospirone, trazadone, zopiclone, and zolpidem.

[0023] Typically, where the drug is a drug for erectile dysfunction, itis selected from one of the following compounds: cialis (IC351),sildenafil, vardenafil, apomorphine, apomorphine diacetate,phentolamine, and yohimbine.

[0024] Typically, where the drug is a drug for migraine headache, it isselected from one of the following compounds: almotriptan, alperopride,codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan,isometheptene, lidocaine, lisuride, metoclopramide, naratriptan,oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid,zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine,diltiazem, doxepin, fluoxetine, lisinopril, methysergide, metoprolol,nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, propanolol,protriptyline, sertraline, timolol, and verapamil.

[0025] Typically, where the drug is a drug for the treatment ofalcoholism, it is selected from one of the following compounds:naloxone, naltrexone, and disulfiram.

[0026] Typically, where the drug is a drug for the treatment ofaddiction it is buprenorphine.

[0027] Typically, where the drug is a muscle relaxant, it is selectedfrom one of the following compounds: baclofen, cyclobenzaprine,orphenadrine, quinine, and tizanidine.

[0028] Typically, where the drug is a nonsteroidal anti-inflammatory, itis selected from one of the following compounds: aceclofenac,alminoprofen, amfenac, aminopropylon, amixetrine, benoxaprofen,bromfenac, bufexamac, carprofen, choline, salicylate, cinchophen,cinmetacin, clopriac, clometacin, diclofenac, etodolac, indoprofen,mazipredone, meclofenamate, piroxicam, pirprofen, and tolfenamate.

[0029] Typically, where the drug is an opioid, it is selected from oneof the following compounds: alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,carbiphene, cipramadol, clonitazene, codeine, dextromoramide,dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate,dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol,lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon,morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine,pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

[0030] Typically, where the drug is an other analgesic it is selectedfrom one of the following compounds: apazone, benzpiperylon,benzydramine, caffeine, clonixin, ethoheptazine, flupirtine, nefopam,orphenadrine, propacetamol, and propoxyphene.

[0031] Typically, where the drug is a stimulant, it is selected from oneof the following compounds: amphetamine, brucine, caffeine,dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine, mazindol,methyphenidate, pemoline, phentermine, and sibutramine.

[0032] In another method aspect of the present invention, a method offorming an aerosol for use in inhalation therapy is provided. The methodinvolves the following steps: (a) heating a substrate coated with acomposition comprising a drug to form a vapor, wherein the coatedcomposition is in the form of a film less than 10μ thick; and, (b)allowing the vapor to cool, thereby forming an aerosol, which is used ininhalation therapy. Preferably, the film thickness is less than 5μ, 4μ,3μ, 2μ, or 1μ thick.

[0033] Typically, the composition is coated on the substrate as a filmthat is between 10μ and 10 nm in thickness. Preferably, the filmthickness is between 5μ and 10 nm, 4μ and 10 nm, 3μ and 10 nm, 2μ and 10nm, or 1μ and 10 nm in thickness.

[0034] Typically, greater than 0.1 mg of the composition is vaporized inless than 100 milliseconds from the start of heating. Preferably, 0.25mg, 0.5 mg, 0.75 mg, or 1 mg of the composition is vaporized in lessthan 100 milliseconds from the start of heating. More preferably, thesame amount of composition list above is vaporized in less than 75milliseconds, 50 milliseconds, 25 milliseconds, or 10 milliseconds fromthe start of heating.

[0035] Typically, the formed aerosol is greater than 10 percent byweight of the drug. Preferably, it is greater than 20 percent by weightof the drug. More preferably, it is greater than 30 percent, 40 percent,50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percentor 97 percent by weight of the drug.

[0036] Typically, the formed aerosol contains less than 10 percent byweight of drug decomposition products. Preferably, it contains less than5 percent by weight of drug decomposition products. More preferably, itcontains less than 3 percent, 2 percent or 1 percent by weight of drugdecomposition products.

[0037] Typically, the drug has a decomposition index less than 0.15.Preferably, the drug has a decomposition index less than 0.10. Morepreferably, the drug has a decomposition index less than 0.05.

[0038] Typically, the drug of the composition is of one of the followingclasses: antibiotics, anticonvulsants, antidepressants, antiemetics,antihistamines, antiparkisonian drugs, antipsychotics, anxiolytics,drugs for erectile dysfunction, drugs for migraine headaches, drugs forthe treatment of alcoholism, drugs for the treatment of addiction,muscle relaxants, nonsteroidal anti-inflammatories, opioids, otheranalgesics and stimulants.

[0039] Typically, where the drug is an antibiotic, it is selected fromone of the following compounds: cefinetazole; cefazolin; cephalexin;cefoxitin; cephacetrile; cephaloglycin; cephaloridine; cephalosporins,such as cephalosporin C; cephalotin; cephamycins, such as cephamycin A,cephamycin B, and cephamycin C; cepharin; cephradine; ampicillin;amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin;amylpenicillin; azidocillin; benzylpenicillin; clometocillin;cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin;penicillins, such as penicillin N, penicillin O, penicillin S,penicillin V; chlorobutin penicillin; dicloxacillin; diphenicillin;heptylpenicillin; and metampicillin.

[0040] Typically, where the drug is an anticonvulsant, it is selectedfrom one of the following compounds: gabapentin, tiagabine, andvigabatrin.

[0041] Typically, where the drug is an antidepressant, it is selectedfrom one of the following compounds: amitriptyline, amoxapine,benmoxine, butriptyline, clomipramine, desipramine, dosulepin, doxepin,imipramine, kitanserin, lofepramine, medifoxamine, mianserin,maprotoline, mirtazapine, nortriptyline, protriptyline, trimipramine,viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine,milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine,acetaphenazine, binedaline, brofaromine, cericlamine, clovoxamine,iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine,selegiline, sibutramine, tranylcypromine, ademetionine, adrafinil,amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone,gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone,nomifensine, ritanserin, roxindole, S-adenosylmethionine, tofenacin,trazodone, tryptophan, venlafaxine, and zalospirone.

[0042] Typically, where the drug is an antiemetic, it is selected fromone of the following compounds: alizapride, azasetron, benzquinamide,bromopride, buclizine, chlorpromazine, cinnarizine, clebopride,cyclizine, diphenhydramine, diphenidol, dolasetron methanesulfonate,droperidol, granisetron, hyoscine, lorazepam, metoclopramide,metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine,scopolamine, triethylperazine, trifluoperazine, triflupromazine,trimethobenzamide, tropisetron, domeridone, and palonosetron.

[0043] Typically, where the drug is an antihistamine, it is selectedfrom one of the following compounds: azatadine, brompheniramine,chlorpheniramine, clemastine, cyproheptadine, dexmedetomidine,diphenhydramine, doxylamine, hydroxyzine, cetrizine, fexofenadine,loratidine, and promethazine.

[0044] Typically, where the drug is an antiparkisonian drug, it isselected one of the following compounds: amantadine, baclofen,biperiden, benztropine, orphenadrine, procyclidine, trihexyphenidyl,levodopa, carbidopa, selegiline, deprenyl, andropinirole, apomorphine,benserazide, bromocriptine, budipine, cabergoline, dihydroergokryptine,eliprodil, eptastigmine, ergoline pramipexole, galanthamine, lazabemide,lisuride, mazindol, memantine, mofegiline, pergolike, pramipexole,propentofylline, rasagiline, remacemide, spheramine, terguride,entacapone, and tolcapone.

[0045] Typically, where the drug is an antipsychotic, it is selectedfrom one of the following compounds: acetophenazine, alizapride,amperozide, benperidol, benzquinamide, bromperidol, buramate,butaperazine, carphenazine, carpipramine, chlorpromazine,chlorprothixene, clocapramine, clomacran, clopenthixol, clospirazine,clothiapine, cyamemazine, droperidol, flupenthixol, fluphenazine,fluspirilene, haloperidol, mesoridazine, metofenazate, molindrone,penfluridol, pericyazine, perphenazine, pimozide, pipamerone,piperacetazine, pipotiazine, prochlorperazine, promazine, remoxipride,sertindole, spiperone, sulpiride, thioridazine, thiothixene,trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine,zuclopenthixol, amisulpride, butaclamol, clozapine, melperone,olanzapine, quetiapine, and risperidone.

[0046] Typically, where the drug is an anxiolytic, it is selected fromone of the following compounds: mecloqualone, medetomidine, metomidate,adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam,loprazolam, midazolam, alpidem, alseroxlon, amphenidone, azacyclonol,bromisovalum, buspirone, calcium N-carboamoylaspartate, captodiamine,capuride, carbcloral, carbromal, chloral betaine, enciprazine,flesinoxan, ipsapiraone, lesopitron, loxapine, methaqualone, methprylon,propanolol, tandospirone, trazadone, zopiclone, and zolpidem.

[0047] Typically, where the drug is a drug for erectile dysfunction, itis selected from one of the following compounds: cialis (IC351),sildenafil, vardenafil, apomorphine, apomorphine diacetate,phentolamine, and yohimbine.

[0048] Typically, where the drug is a drug for migraine headache, it isselected from one of the following compounds: almotriptan, alperopride,codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan,isometheptene, lidocaine, lisuride, metoclopramide, naratriptan,oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid,zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine,diltiazem, doxepin, fluoxetine, lisinopril, methysergide, metoprolol,nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, propanolol,protriptyline, sertraline, timolol, and verapamil.

[0049] Typically, where the drug is a drug for the treatment ofalcoholism, it is selected from one of the following compounds:naloxone, naltrexone, and disulfiram.

[0050] Typically, where the drug is a drug for the treatment ofaddiction it is buprenorphine.

[0051] Typically, where the drug is a muscle relaxant, it is selectedfrom one of the following compounds: baclofen, cyclobenzaprine,orphenadrine, quinine, and tizanidine.

[0052] Typically, where the drug is a nonsteroidal anti-inflammatory, itis selected from one of the following compounds: aceclofenac,alminoprofen, amfenac, aminopropylon, amixetrine, benoxaprofen,bromfenac, bufexamac, carprofen, choline, salicylate, cinchophen,cinmetacin, clopriac, clometacin, diclofenac, etodolac, indoprofen,mazipredone, meclofenamate, piroxicam, pirprofen, and tolfenamate.

[0053] Typically, where the drug is an opioid, it is selected from oneof the following compounds: alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,carbiphene, cipramadol, clonitazene, codeine, dextromoramide,dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate,dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol,lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon,morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine,pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

[0054] Typically, where the drug is an other analgesic it is selectedfrom one of the following compounds: apazone, benzpiperylon,benzydramine, caffeine, clonixin, ethoheptazine, flupirtine, nefopam,orphenadrine, propacetamol, and propoxyphene.

[0055] Typically, where the drug is a stimulant, it is selected from oneof the following compounds: amphetamine, brucine, caffeine,dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine, mazindol,methyphenidate, pemoline, phentermine, and sibutramine.

[0056] In another method aspect of the present invention, a method offorming an aerosol for use in inhalation therapy is provided. The methodinvolves the following steps: (a) heating a substrate-coated with acomposition comprising a drug to form a vapor in less than 100milliseconds, wherein the vapor has a mass greater than 0.1 mg; and, (b)allowing the vapor to cool, thereby forming an aerosol, which is used ininhalation therapy. Preferably, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg of thecomposition is vaporized in less than 100 milliseconds from the start ofheating. More preferably, the same amount of composition list above isvaporized in less than 75 milliseconds, 50 milliseconds, 25milliseconds, or 10 milliseconds from the start of heating.

[0057] Typically, the formed aerosol is greater than 10 percent byweight of the drug. Preferably, it is greater than 20 percent by weightof the drug. More preferably, it is greater than 30 percent, 40 percent,50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percentor 97 percent by weight of the drug.

[0058] Typically, the formed aerosol contains less than 10 percent byweight of drug decomposition products. Preferably, it contains less than5 percent by weight of drug decomposition products. More preferably, itcontains less than 3 percent, 2 percent or 1 percent by weight of drugdecomposition products.

[0059] Typically, the drug has a decomposition index less than 0.15.Preferably, the drug has a decomposition index less than 0.10. Morepreferably, the drug has a decomposition index less than 0.05.

[0060] Typically, the drug of the composition is of one of the followingclasses: antibiotics, anticonvulsants, antidepressants, antiemetics,antihistamines, antiparkisonian drugs, antipsychotics, anxiolytics,drugs for erectile dysfunction, drugs for migraine headaches, drugs forthe treatment of alcoholism, drugs for the treatment of addiction,muscle relaxants, nonsteroidal anti-inflammatories, opioids, otheranalgesics and stimulants.

[0061] Typically, where the drug is an antibiotic, it is selected fromone of the following compounds: cefnetazole; cefazolin; cephalexin;cefoxitin; cephacetrile; cephaloglycin; cephaloridine; cephalosporins,such as cephalosporin C; cephalotin; cephamycins, such as cephamycin A,cephamycin B, and cephamycin C; cepharin; cephradine; ampicillin;amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin;amylpenicillin; azidocillin; benzylpenicillin; clometocillin;cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin;penicillins, such as penicillin N, penicillin O, penicillin S,penicillin V; chlorobutin penicillin; dicloxacillin; diphenicillin;heptylpenicillin; and metampicillin.

[0062] Typically, where the drug is an anticonvulsant, it is selectedfrom one of the following compounds: gabapentin, tiagabine, andvigabatrin.

[0063] Typically, where the drug is an antidepressant, it is selectedfrom one of the following compounds: amitriptyline, amoxapine,benmoxine, butriptyline, clomipramine, desipramine, dosulepin, doxepin,imipramine, kitansenn, lofepramine, medifoxamine, mianserin,maprotoline, mirtazapine, nortriptyline, protriptyline, trimipramine,viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine,milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine,acetaphenazine, binedaline, brofaromine, cericlamine, clovoxamine,iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine,selegiline, sibutramine, tranylcypromine, ademetionine, adrafinil,amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone,gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone,nomifensine, ritanserin, roxindole, S-adenosylmethionine, tofenacin,trazodone, tryptophan, venlafaxine, and zalospirone.

[0064] Typically, where the drug is an antiemetic, it is selected fromone of the following compounds: alizapride, azasetron, benzquinamide,bromopride, buclizine, chlorpromazine, cinnarizine, clebopride,cyclizine, diphenhydramine, diphenidol, dolasetron methanesulfonate,droperidol, granisetron, hyoscine, lorazepam, metoclopramide,metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine,scopolamine, triethylperazine, trifluoperazine, triflupromazine,trimethobenzamide, tropisetron, domeridone, and palonosetron.

[0065] Typically, where the drug is an antihistamine, it is selectedfrom one of the following compounds: azatadine, brompheniramine,chlorpheniramine, clemastine, cyproheptadine, dexmedetomidine,diphenhydramine, doxylamine, hydroxyzine, cetrizine, fexofenadine,loratidine, and promethazine.

[0066] Typically, where the drug is an antiparkisonian drug, it isselected one of the following compounds: amantadine, baclofen,biperiden, benztropine, orphenadrine, procyclidine, trihexyphenidyl,levodopa, carbidopa, selegiline, deprenyl, andropinirole, apomorphine,benserazide, bromocriptine, budipine, cabergoline, dihydroergokryptine,eliprodil, eptastigmine, ergoline pramipexole, galanthamine, lazabemide,lisuride, mazindol, memantine, mofegiline, pergolike, pramipexole,propentofylline, rasagiline, remacemide, spheramine, terguride,entacapone, and tolcapone.

[0067] Typically, where the drug is an antipsychotic, it is selectedfrom one of the following compounds: acetophenazine, alizapride,amperozide, benperidol, benzquinamide, bromperidol, buramate,butaperazine, carphenazine, carpipramine, chlorpromazine,chlorprothixene, clocapramine, clomacran, clopenthixol, clospirazine,clothiapine, cyamemazine, droperidol, flupenthixol, fluphenazine,fluspirilene, haloperidol, mesoridazine, metofenazate, molindrone,penfluridol, pericyazine, perphenazine, pimozide, pipamerone,piperacetazine, pipotiazine, prochlorperazine, promazine, remoxipride,sertindole, spiperone, sulpiride, thioridazine, thiothixene,trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine,zuclopenthixol, amisulpride, butaclamol, clozapine, melperone,olanzapine, quetiapine, and risperidone.

[0068] Typically, where the drug is an anxiolytic, it is selected fromone of the following compounds: mecloqualone, medetomidine, metomidate,adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam,loprazolam, midazolam, alpidem, alseroxlon, amphenidone, azacyclonol,bromisovalum, buspirone, calcium N-carboamoylaspartate, captodiamine,capuride, carbcloral, carbromal, chloral betaine, enciprazine,flesinoxan, ipsapiraone, lesopitron, loxapine, methaqualone, methprylon,propanolol, tandospirone, trazadone, zopiclone, and zolpidem.

[0069] Typically, where the drug is a drug for erectile dysfunction, itis selected from one of the following compounds: cialis (IC351),sildenafil, vardenafil, apomorphine, apomorphine diacetate,phentolamine, and yohimbine.

[0070] Typically, where the drug is a drug for migraine headache, it isselected from one of the following compounds: almotriptan, alperopride,codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan,isometheptene, lidocaine, lisuride, metoclopramide, naratriptan,oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid,zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine,diltiazem, doxepin, fluoxetine, lisinopril, methysergide, metoprolol,nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, propanolol,protriptyline, sertraline, timolol, and verapamil.

[0071] Typically, where the drug is a drug for the treatment ofalcoholism, it is selected from one of the following compounds:naloxone, naltrexone, and disulfiram.

[0072] Typically, where the drug is a drug for the treatment ofaddiction it is buprenorphine.

[0073] Typically, where the drug is a muscle relaxant, it is selectedfrom one of the following compounds: baclofen, cyclobenzaprine,orphenadrine, quinine, and tizanidine.

[0074] Typically, where the drug is a nonsteroidal anti-inflammatory, itis selected from one of the following compounds: aceclofenac,alminoprofen, amfenac, aminopropylon, amixetrine, benoxaprofen,bromfenac, bufexamac, carprofen, choline, salicylate, cinchophen,cinmetacin, clopriac, clometacin, diclofenac, etodolac, indoprofen,mazipredone, meclofenamate, piroxicam, pirprofen, and tolfenamate.

[0075] Typically, where the drug is an opioid, it is selected from oneof the following compounds: alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,carbiphene, cipramadol, clonitazene, codeine, dextromoramide,dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate,dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol,lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon,morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine,pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

[0076] Typically, where the drug is an other analgesic it is selectedfrom one of the following compounds: apazone, benzpiperylon,benzydramine, caffeine, clonixin, ethoheptazine, flupirtine, nefopam,orphenadrine, propacetamol, and propoxyphene.

[0077] Typically, where the drug is a stimulant, it is selected from oneof the following compounds: amphetamine, brucine, caffeine,dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine, mazindol,methyphenidate, pemoline, phentermine, and sibutramine.

BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Further features and advantages will become apparent from thefollowing description of various examples of the invention, asillustrated in the accompanying drawings in which:

[0079]FIG. 1 is a schematic diagram of the overall system for conductingexperiments using a laboratory example of a device of the presentinvention;

[0080]FIG. 2 is a top, right end and front perspective view of theexample depicted in FIG. 1;

[0081]FIG. 3 is a partial cross-sectional and partial schematic sideview of the example shown in FIG. 2;

[0082]FIG. 4 is a partial cross-sectional and partial schematic end viewof the example shown in FIG. 2;

[0083]FIG. 5 is a partial cross-sectional and partial schematic top viewof the example shown in FIG. 2;

[0084]FIG. 6 is a schematic cross-sectional side view of an alternateexample of the device of the present invention using an annunciatingdevice;

[0085]FIG. 7 is a top, left end and front perspective views of theremovable sub-assembly containing the compound and a movable slide ofthe example shown in FIG. 2 showing the sub-assembly being mountedwithin the slide;

[0086]FIG. 8 is a schematic view of the heating element of the exampleshown in FIG. 2 showing the electric drive circuit;

[0087]FIG. 9 is a schematic side view of a second example of the presentinvention using a venturi tube;

[0088]FIG. 10 is a schematic side view of a fourth example of thepresent invention using a thin-walled tube coated with the compound;

[0089]FIG. 11 is a schematic side end view of the example shown in FIG.10;

[0090]FIG. 12 is a schematic side end view of the example shown in FIG.10 showing an inductive heating system generating an alternatingmagnetic field;

[0091]FIG. 13 is a schematic side view of an alternate example of thatshown in FIG. 10 using a flow restrictor within the thin-walled tube;

[0092]FIG. 14 is a schematic side view of a fifth example of the presentinvention using an expandable container for the compound;

[0093]FIG. 15 is a schematic side view of a sixth example of the presentinvention using a container for the compound in an inert atmosphere;

[0094]FIG. 16 is a schematic side view of the example shown in FIG. 15using a re-circulation of the inert atmosphere over the compound'ssurface;

[0095]FIG. 17 is a schematic side view of a seventh example of thepresent invention using a tube containing particles coated with thecompound;

[0096]FIG. 18 is a schematic side view of the example shown in FIG. 17using a heating system to heat the gas passing over the coatedparticles;

[0097]FIG. 19 is a schematic side view of an eighth example of thepresent invention referred to herein as the “oven device”;

[0098]FIG. 20 is a schematic side view of an ninth example of thepresent invention using gradient heating;

[0099]FIG. 21 is a schematic side view of a tenth example of the presentinvention using a fine mesh screen coated with the compound;

[0100]FIG. 22 is a top, right end and front perspective view of theexample shown in FIG. 21;

[0101]FIG. 23 is a plot of the rate of aggregation of smaller particlesinto larger ones;

[0102]FIG. 24 is a plot of the coagulation coefficient (K) versusparticle size of the compound;

[0103]FIG. 25 is a plot of vapor pressure of various compounds, e.g.,diphenyl ether, hexadecane, geranyl formate and caproic acid, versustemperature;

[0104]FIG. 26 is a plot of blood levels for both the IV dose and theinhalation dose administered to various dogs during the experimentsusing the system shown in FIG. 1;

[0105]FIG. 27 is a plot of calculated and experimental mass mediandiameter (MMD) versus compound mass in the range of 10 to 310 pg;

[0106]FIG. 28 is a plot of calculated and experimental MMD versuscompound mass in the range of 10 to 310 μg; and

[0107]FIG. 29 is a plot of the theoretical size (diameter) of an aerosolas a function of the ratio of the vaporized compound to the volume ofthe mixing gas.

DETAILED DESCRIPTION

[0108] Definitions

[0109] “Aerodynamic diameter” of a given particle refers to the diameterof a spherical droplet with a density of 1 g/mL (the density of water)that has the same settling velocity as the given particle.

[0110] “erosol” refers to a suspension of solid or liquid particles in agas.

[0111] “Decomposition index” refers to a number derived from an assaydescribed in Example 9. The number is determined by substracting thepercent purity of the generated aerosol from 1.

[0112] “Drug” refers to any chemical compound that is used in theprevention, diagnosis, treatment, or cure of disease, for the relief ofpain, or to control or improve any physiological or pathologicaldisorder in humans or animals. Such compounds are oftentimes listed inthe Physician's Desk Reference (Medical Economics Company, Inc. atMontvale, N.J., 56^(th) edition, 2002), which is herein incorporated byreference.

[0113] Exemplary drugs include the following: cannabanoid extracts fromcannabis, THC, ketorolac, fentanyl, morphine, testosterone, ibuprofen,codeine, nicotine, Vitamin A, Vitamin E acetate, Vitamin E,nitroglycerin, pilocarpine, mescaline, testosterone enanthate, menthol,phencaramkde, methsuximide, eptastigmine, promethazine, procaine,retinol, lidocaine, trimeprazine, isosorbide dinitrate, timolol,methyprylon, etamiphyllin, propoxyphene, salmetrol, vitamin E succinate,methadone, oxprenolol, isoproterenol bitartrate, etaqualone, Vitamin D3,ethambutol, ritodrine, omoconazole, cocaine, lomustine, ketamine,ketoprofen, cilazaprol, propranolol, sufentanil, metaproterenol,prentoxapylline, testosterone proprionate, valproic acid, acebutolol,terbutaline, diazepam, topiramate, pentobarbital, alfentanil HCl,papaverine, nicergoline, fluconazole, zafirlukast, testosterone acetate,droperidol, atenolol, metoclopramide, enalapril, albuterol, ketotifen,isoproterenol, amiodarone HCl, zileuton, midazolam, oxycodone,cilostazol, propofol, nabilone, gabapentin, famotidine, lorezepam,naltrexone, acetaminophen, sumatriptan, bitolterol, nifedipine,Phenobarbital, phentolamine, 13-cis retinoic acid, droprenilamin HCl,amlodipine, caffeine, zopiclone, tramadol HCl, pirbuterol naloxone,meperidine HCl, trimethobenzamide, nalmefene, scopolamine, sildenafil,carbamazepine, procaterol HCl, methysergide, glutathione, olanzapine,zolpidem, levorphanol, buspirone and mixtures thereof.

[0114] Typically, the drug of the composition is of one of the followingclasses: antibiotics, anticonvulsants, antidepressants, antiemetics,antihistamines, antiparkisonian drugs, antipsychotics, anxiolytics,drugs for erectile dysfunction, drugs for migraine headaches, drugs forthe treatment of alcoholism, drugs for the treatment of addiction,muscle relaxants, nonsteroidal anti-inflammatories, opioids, otheranalgesics, cannabanoids, and stimulants.

[0115] Typically, where the drug is an antibiotic, it is selected fromone of the following compounds: cefinetazole; cefazolin; cephalexin;cefoxitin; cephacetrile; cephaloglycin; cephaloridine; cephalosporins,such as cephalosporin C; cephalotin; cephamycins, such as cephamycin A,cephamycin B, and cephamycin C; cepharin; cephradine; ampicillin;amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin;amylpenicillin; azidocillin; benzylpenicillin; clometocillin;cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin;penicillins, such as penicillin N, penicillin O, penicillin S,penicillin V; chlorobutin penicillin; dicloxacillin; diphenicillin;heptylpenicillin; and metampicillin.

[0116] Typically, where the drug is an anticonvulsant, it is selectedfrom one of the following compounds: gabapentin, tiagabine, andvigabatrin.

[0117] Typically, where the drug is an antidepressant, it is selectedfrom one of the following compounds: amitriptyline, amoxapine,benmoxine, butriptyline, clomipramine, desipramine, dosulepin, doxepin,imipramine, kitanserin, lofepramine, medifoxamine, mianserin,maprotoline, mirtazapine, nortriptyline, protriptyline, trimipramine,viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine,milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine,acetaphenazine, binedaline, brofaromine, cericlamine, clovoxamine,iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine,selegiline, sibutramine, tranylcypromine, ademetionine, adrafinil,amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone,gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone,nomifensine, ritanserin, roxindole, S-adenosylmethionine, tofenacin,trazodone, tryptophan, venlafaxine, and zalospirone.

[0118] Typically, where the drug is an antiemetic, it is selected fromone of the following compounds: alizapride, azasetron, benzquinamide,bromopride, buclizine, chlorpromazine, cinnarizine, clebopride,cyclizine, diphenhydramine, diphenidol, dolasetron methanesulfonate,dronabinol, droperidol, granisetron, hyoscine, lorazepam,metoclopramide, metopimazine, ondansetron, perphenazine, promethazine,prochlorperazine, scopolamine, triethylperazine, trifluoperazine,triflupromazine, trimethobenzamide, tropisetron, domeridone, andpalonosetron.

[0119] Typically, where the drug is an antihistamine, it is selectedfrom one of the following compounds: azatadine, brompheniramine,chlorpheniramine, clemastine, cyproheptadine, dexmedetomidine,diphenhydramine, doxylamine, hydroxyzine, cetrizine, fexofenadine,loratidine, and promethazine.

[0120] Typically, where the drug is an antiparkisonian drug, it isselected one of the following compounds: amantadine, baclofen,biperiden, benztropine, orphenadrine, procyclidine, trihexyphenidyl,levodopa, carbidopa, selegiline, deprenyl, andropinirole, apomorphine,benserazide, bromocriptine, budipine, cabergoline, dihydroergokryptine,eliprodil, eptastigmine, ergoline pramipexole, galanthamine, lazabemide,lisuride, mazindol, memantine, mofegiline, pergolike, pramipexole,propentofylline, rasagiline, remacemide, spheramine, terguride,entacapone, and tolcapone.

[0121] Typically, where the drug is an antipsychotic, it is selectedfrom one of the following compounds: acetophenazine, alizapride,amperozide, benperidol, benzquinamide, bromperidol, buramate,butaperazine, carphenazine, carpipramine, chlorpromazine,chlorprothixene, clocapramine, clomacran, clopenthixol, clospirazine,clothiapine, cyamemazine, droperidol, flupenthixol, fluphenazine,fluspirilene, haloperidol, mesoridazine, metofenazate, molindrone,penfluridol, pericyazine, perphenazine, pimozide, pipamerone,piperacetazine, pipotiazine, prochlorperazine, promazine, remoxipride,sertindole, spiperone, sulpiride, thioridazine, thiothixene,trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine,zuclopenthixol, amisulpride, butaclamol, clozapine, melperone,olanzapine, quetiapine, and risperidone.

[0122] Typically, where the drug is an anxiolytic, it is selected fromone of the following compounds: mecloqualone, medetomidine, metomidate,adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam,loprazolam, midazolam, alpidem, alseroxlon, amphenidone, azacyclonol,bromisovalum, buspirone, calcium N-carboamoylaspartate, captodiamine,capuride, carbcloral, carbromal, chloral betaine, enciprazine,flesinoxan, ipsapiraone, lesopitron, loxapine, methaqualone, methprylon,propanolol, tandospirone, trazadone, zopiclone, and zolpidem.

[0123] Typically, where the drug is a drug for erectile dysfunction, itis selected from one of the following compounds: cialis (IC351),sildenafil, vardenafil, apomorphine, apomorphine diacetate,phentolamine, and yohimbine.

[0124] Typically, where the drug is a drug for migraine headache, it isselected from one of the following compounds: almotriptan, alperopride,codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan,isometheptene, lidocaine, lisuride, metoclopramide, naratriptan,oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid,zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine,diltiazem, doxepin, fluoxetine, lisinopril, methysergide, metoprolol,nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, propanolol,protriptyline, sertraline, timolol, and verapamil.

[0125] Typically, where the drug is a drug for the treatment ofalcoholism, it is selected from one of the following compounds:naloxone, naltrexone, and disulfiram.

[0126] Typically, where the drug is a drug for the treatment ofaddiction it is buprenorphine.

[0127] Typically, where the drug is a muscle relaxant, it is selectedfrom one of the following compounds: baclofen, cyclobenzaprine,orphenadrine, quinine, and tizanidine.

[0128] Typically, where the drug is a nonsteroidal anti-inflammatory, itis selected from one of the following compounds: aceclofenac,alminoprofen, amfenac, aminopropylon, amixetrine, benoxaprofen,bromfenac, bufexamac, carprofen, choline, salicylate, cinchophen,cinmetacin, clopriac, clometacin, diclofenac, etodolac, indoprofen,mazipredone, meclofenamate, piroxicam, pirprofen, and tolfenamate.

[0129] Typically, where the drug is an opioid, it is selected from oneof the following compounds: alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,carbiphene, cipramadol, clonitazene, codeine, dextromoramide,dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate,dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol,lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon,morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine,pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

[0130] Typically, where the drug is an other analgesic it is selectedfrom one of the following compounds: apazone, benzpiperylon,benzydramine, caffeine, clonixin, ethoheptazine, flupirtine, nefopam,orphenadrine, propacetamol, and propoxyphene.

[0131] Typically, where the drug is a cannabanoid, it istetrahydrocannabinol (e.g., delta-8 or delta-9).

[0132] Typically, where the drug is a stimulant, it is selected from oneof the following compounds: amphetamine, brucine, caffeine,dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine, mazindol,methyphenidate, pemoline, phentermine, and sibutramine.

[0133] “Drug degradation product” refers to a compound resulting from achemical modification of a drug. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

[0134] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refersto the aerodynamic diameter for which half the particulate mass of theaerosol is contributed by particles with an aerodynamic diameter largerthan the MMAD and half by particles with an aerodynamic diameter smallerthan the MMAD.

[0135] “Stable aerosol” refers to an aerosol where the MMAD of itsconstituent particles does not vary by more than 50% over a set periodof time. For example, an aerosol with an MMAD of 100 nm is stable over 1s, if at a time 1 second later it has an MMAD between 50 nm and 150 nm.Preferably, the MMAD does not vary by more than 25% over a set period oftime. More preferably, the MMAD does not vary by more than 20%, 15%, 10%or 5% over time.

[0136] Aerosolization Device

[0137] Example 1 is described in terms of an in vivo dog experiment. Theexample, however, is easily modified to suit human inhalation primarilythrough increasing airflow through it.

[0138] Referring to FIGS. 1-8, a first example (1) of an aerosolizationdevice of the present invention will be described. The device 1 as shownin FIG. 1 is operably connected to flow meter 4 (e.g. , a TSI 4100 flowmeter). The readings from flow meter 4 are fed to the electronics withinchassis 8 shown in FIG. 2. Flow meter 4 is shown in FIG. 1 within adotted line to indicate housing 10. Device controller 20 includesChembook model #N30W laptop computer having actuator switch 22 (FIG. 3)and National Instruments I/O Board (model #SC2345) (not shown) thatinterfaces with computer 20 to control device 1 and to control therecording of all data collected during the experiments. A softwareprogram to carry out these functions was developed using NationalInstruments' Labview software program.

[0139] Connection between device 1 and the I/O board is accomplishedwith a cable (e.g., DB25, not shown). A standard power supply (e.g.,Condor F15-15-A+ not shown) delivers power to device 1. Inhalationcontroller 30 is used to control the rate and volume of inhalationthrough device 1 into an anesthetized dog through an endotracheal tube34. Controller 30 has a programmable breath hold delay, at the end ofwhich, exhaust valve 40 in exhaust line 42 opens and the dog is allowedto exhale. Filter 50 in line 42 measures the amount of exhaust and itscomposition to monitor any exhaled drug. The source air through inletline 54, inlet valve 58, flow meter 4 and inlet orifice 59 is from acompressed air cylinder (not shown).

[0140] Now referring to FIGS. 3-5 and 7, a dose of compound 60 isdeposited onto thin, stainless steel foil 64 so that the thickness ofcompound 60 is less than 10 microns. In most cases, compound 60 isdeposited by making a solution of the compound with an organic solvent.This mixture is then applied to the foil substrate with an automatedpump system. As shown, the size of the entire foil 64 (e.g., alloy of302 or 304 with 0.004 in. thickness) is 0.7 by 2.9 inches and the areain which compound 60 is deposited is 0.35 by 1.6 inches. Other foilmaterials can be used but stainless steel has an advantage over othermaterials like aluminum in that it has a much lower thermal conductivityvalue, while not appreciably increasing the thermal mass. A low thermalconductivity is helpful because the heat generated in foil 64 shouldstay in the area of interest (i.e., the heating/vaporization zone 70).Foil 64 should have a constant cross section, because otherwise theelectrical currents induced by the heater will not be uniform. Foil 64is held in frame 68, made so that the trailing edge of foil 64 has nolip on movable slide 78 and so compound 60, once mixed with the air, isfree in a downstream direction as indicated by arrow 127 of FIG. 3.Frame 68 is typically made of a non-conductive material to withstandmoderate heat (e.g., 200° C.) and to be non-chemically reactive with thecompound (e.g., DELRIN AF®, a copolymer of acetal and TEFLON®).

[0141] Sub-assembly 80, shown in FIG. 7, consists of frame 68 havingcompound (60) coated foil 64 mounted therein. Sub-assembly 80 is securedwithin movable slide 78 by setting each of the downstream, tapered endsof frame 68 to abut against small rods 86 protruding from eachdownstream end of slide 78, as shown in FIG. 7. Slide 78 is driven bystepper motor 88, shown in FIG. 3, that moves sub-assembly 80 containingcompound 60 along the longitudinal axis of example 1. This, in turn,moves stainless steel foil 64 through an alternating magnetic field. (Itis preferable for the magnetic field to be confined withinheating/vaporization zone 70, shown in FIG. 5, as in this laboratoryexample.) Ferrite toroid 90 is used to direct the magnetic field and isplaced below foil 64 (e.g., approximately 0.05 inches below). As shownin FIG. 5, heated area 70 is approximately 0.15 by 0.4 inches, with thesmaller dimension along the direction of travel from left to right(i.e., from the upstream to the downstream ends of device 1) and thelarge dimension across the direction of travel (i.e., the width ofdevice 1).

[0142] Foil 64 functions as both a substrate for the drug to bedelivered to the subject and the heating element for the vaporization ofthe drug. Heating element 64 is heated primarily by eddy currentsinduced by an alternating magnetic field. The alternating magnetic fieldis produced in ferrite toroid 90 (e.g., from Fair-Rite Company) withslit 94 (e.g., 0.10 in. wide), which was wrapped with coil 98 of coppermagnet wire. When an alternating current is passed through coil 98, analternating magnetic field is produced in ferrite toroid 90. A magneticfield fills the gap formed by slit 94 and magnetic field fringe lines100, shown in FIGS. 5 and 6, extend out from toroid 90. The magneticfield line fringe lines 100 intersect heating element 64. When using aferrite core, the alternating frequency of the field is limited to below1 MHz. In this device, a frequency between 100 and 300 kHz is typicallyused.

[0143] The location and geometry of the eddy currents determine wherefoil 64 will be heated. Since magnetic field fringe lines 100 passthrough foil 64 twice, once leaving ferrite toroid 90 and oncereturning, two rings of current are produced, and in oppositedirections. One of the rings is formed around magnetic field lines 100that leave toroid 90 and the other ring forms around magnetic fieldlines 100 that return toroid 90. The rings of current overlap directlyover the center of slit 94. Since they were in opposite directions, theysum together. The greatest heating effect is therefore produced over thecenter of slit 94.

[0144] Slide 78 and its contents are housed in airway 102 made up ofupper airway section 104 and lower airway section 108 shown in FIG. 3.Upper airway section 104 is removable and allows the insertion ofmovable slide 78, sub-assembly 80 and foil 64. Lower airway section 108is mounted on top of chassis 8 that houses the electronics (not shown),magnetic field generator 110, stepper motor 88 and position sensors (notshown). Referring again to FIG. 1, mounted in upper airway section 104is upstream passage 120 and inlet orifice 59 that couples upper airwaysection 104 to flow meter 4. The readings from the flow meter 4 are fedto the electronics housed in chassis 8. Additionally, at the downstreamend of airway passage 102, outlet 124 is connected to mouthpiece 126.During administration of compound 60 to the dog, when joined to thesystem, air is forced through inlet line 54, flow meter 4, airway 102,and outlet 124 into the dog.

[0145] Additionally, a pyrometer at the end of TC2 line 130 is locatedwithin airway 102 and is used to measure the temperature of foil 64.Because of the specific geometry of the example shown in FIGS. 1-7, thetemperature reading of foil 64 is taken after heating zone 70.Calibration of the thermal decay between heating zone 70 and themeasurement area is required. Temperature data is collected and used forquality control and verification and not to control any heatingparameters. A second temperature sensor is located at the end of TC1line 132 in outlet 124 and is used to monitor the temperature of the airdelivered to the dog.

[0146] In a preferred example of the experimental device, removableblock 140, mounted on upper airway section 104, restricts across-sectional area of airway 102 and provides a specific mixinggeometry therein. In this preferred example, airway 140 lowers the roofof upper airway section 104 (e.g., to within 0.04 inch of) with respectto foil 64. Additionally, block 140 contains baffles (e.g., 31 steelrods 0.04 in. in diameter, not shown). The rods are orientedperpendicular to the foil and extend from the top of upper airwaysection 104 to within a small distance of the foil (e.g., 0.004 in.).The rods are placed in a staggered pattern and have sharp, squared offends, which cause turbulence as air passes around them. This turbulanceassures complete mixing of vaporized compounds with air passing throughthe device.

[0147] A second example (150) of an aerosolization device of the presentinvention, in which the cross-sectional area is also restricted alongthe gas/vapor mixing area, will be described in reference to FIG. 9. Inthis example, venturi tube 152 within housing 10 having inlet 154,outlet 156 includes a throat 158 between inlet 154 and outlet 156, whichis used to restrict the gas flow through venturi tube 152. Additionally,a controller 160 is designed to control the flow of air passing througha valve 164 based on readings from the thermocouple 168 of thetemperature of the air, which can be controlled by heater 166.

[0148] Block 140 is located directly over heating zone 70 and creates aheating/vaporization/mixing zone. Prior to commencing aerosolgeneration, slide 78 is in the downstream position. Slide 78, with itscontents, is then drawn upstream into this heating/vaporization/mixingzone 70 as energy is applied to foil 64 through the inductive heatersystem described in detail below.

[0149] The device of the present invention is optionally equipped withan annunciating device. One of the many functions for the annunciatingdevice is to alert the operator of the device that a compound is notbeing vaporized or is being improperly vaporized. The annunciatingdevice can also be used to alert the operator that the gas flow rate isoutside a desired range. FIG. 6 is a schematic diagram illustrating athird example of a hand held aerosolization device 180 of the presentinvention. As shown, device 180 includes many of the components ofdevice 150, discussed above, and additionally includes an annunciatingdevice 170. During the use of device 180 in which the patient'sinhalation rate controls the airflow rate, a signal from annunciatingdevice 170 would alert the patient to adjust the inhalation rate to thedesired range. In this case, controller 160 would be connected toannunciating device 170 to send the necessary signal that the flow ratewas not within the desired range.

[0150] The induction drive circuit 190 shown in FIG. 8 is used to drivethe induction-heating element of device 1. The purpose of circuit 190 isto produce an alternating current in drive coil 98 wrapped aroundferrite core 90. Circuit 190 consists of two P-channel transistors 200and two N-channel MOSFET transistors 202 arranged in a bridgeconfiguration. MOSFET transistors 200 and 202 connected to clock pulsegenerator 219 are turned on and off in pairs by D-type flip-flop 208through MOSFET transistor drive circuit 210. D-type flip-flop 208 iswired to cause the Q output of the flip-flop to alternately change statewith the rising edge of the clock generation signal. One pair of MOSFETtransistors 200 is connected to the Q output on D-type flip-flop 208 andthe other pair, 202, is connected to the Q-not output of flip-flop 208.When Q is high (5 Volts), a low impedance connection is made between theD.C. power supply (not shown) and the series combination of drive coil98 and the capacitor through the pair of MOSFET transistors 200controlled by the Q output. When D-type flip-flop 208 changes state andQ-not is high, the low impedance connection from the power supply to theseries combination drive coil 98 and capacitor 220 is reversed. Sinceflip-flop 208 changes state on the rising edge of the clock generationsignal, two flip-flop changes are required for one complete drive cycleof the induction-heating element. The clock generation signal istypically set at twice the resonant frequency of the series combinationof drive coil 90 and capacitor 220. The clock signal frequency can bemanually or automatically set.

[0151] A second example (150) of an aerosolization device of the presentinvention, in which the cross-sectional area is also restricted alongthe gas/vapor mixing area, will be described in reference to FIG. 9. Inthis example, venturi tube 152 within housing 10 having inlet 154,outlet 156 and throat 158 between inlet 154 and outlet 156 is used torestrict the gas flow through venturi tube 152. Controller 160 isdesigned to control the flow of air passing through valve 164 based onreadings from the thermocouple 168 of the temperature of the air as aresult of heater 166.

[0152] A fourth example (300) of an aerosolization device of the presentinvention will be described in reference to FIGS. 10 and 11. A gasstream is passed into thin walled tube 302 having a coating (310) ofcompound 60 on its inside. The flow rate of the gas stream is controlledby valve 314. The device of example 300, as with others, allows forrapid heat-up using a resistive heating system (320) while controllingthe flow direction of vaporized compound. After activating heatingsystem 320 with actuator 330, current is passed along tube 302 in theheating/vaporization zone 340 as the carrier gas (e.g., air, N₂ and thelike) is passed through tube 302 and mixes with the resulting vapor.

[0153]FIG. 12 shows an alternative heating system to resistive heatingsystem 320 used in connection with the fourth example. In this case,inductive heating system 350 consists of a plurality of ferrites 360 forconducting the magnetic flux to vaporize compound 310.

[0154]FIG. 13 shows a variation on the fourth example in which flowrestrictor 370 is mounted within thin-walled tube 302 by means ofsupport 374 within a housing (not shown) to increase the flow of mixinggas across the surface of compound 310.

[0155] A fifth example 400 of an aerosolization device of the presentinvention will be described in reference to FIG. 14. For this example,compound 60 is placed within expandable container 402 (e.g., a foilpouch) and is heated by resistance heater 406, which is activated byactuator 410 as shown in FIG. 14. The vaporized compound generated isforced into container 420 through outlet passage 440 and mixed with thegas flowing through tube 404. Additional steps are taken, whennecessary, to preclude or retard decomposition of compound 60. One suchstep is the removal or reduction of oxygen around 60 during the heat upperiod. This can be accomplished, for example, by sealing-the smallcontainer housing in an inert atmosphere.

[0156] A sixth example 500 of an aerosolization device of the presentinvention will be described in reference to FIG. 15. Compound 60 isplaced in an inert atmosphere or under a vacuum in container 502 withinhousing 10 and is heated by resistance heater 504 upon being activatedby actuator 508 as shown in FIG. 15. Once compound 60 has becomevaporized it can then be ejected through outlet passage 510 into the airstream passing through tube 520.

[0157]FIG. 16 shows a variation of device 500 in which fan 530recirculates the inert atmosphere over the surface of compound 60. Theinert gas from a compressed gas cylinder (not shown) enters throughinlet 540 and one-way valve 550 and exits through outlet passage 510into tube 502.

[0158] A seventh example (600) of an aerosolization device of thepresent invention will be described in reference to FIG. 17. A compound(not shown), such as compound 60 discussed above, is deposited onto asubstrate in the form of discrete particles 602 (e.g., aluminum oxide(alumina), silica, coated silica, carbon, graphite, diatomaceous earth,and other packing materials commonly used in gas chromatography). Thecoated particles are placed within first tube 604, sandwiched betweenfilters 606 and 608, and heated by resistance heater 610, which isactivated by actuator 620. The resulting vapor from tube 604 is combinedwith the air or other gas passing through second tube 625.

[0159]FIG. 18 shows a variation of device 600 in which resistance heater630 heats the air prior to passing through first tube 604 and overdiscrete particles 602.

[0160] An eighth example 700 of an aerosolization device of the presentinvention will be described in reference to FIG. 19. Compound 60 isdeposited into chamber 710 and is heated by resistance heater 715, whichis activated by actuator 720. Upon heating, some of compound 60 isvaporized and ejected from chamber 710 by passing an inert gas enteringhousing 10 through inert gas inlet 725 and valve 728 across the surfaceof the compound. The mixture of inert gas and vaporized compound passesthrough passage 730 and is then mixed with a gas passing through tube735.

[0161] A ninth example 800 of an aerosolization device of the presentinvention will be described in reference to FIG. 20. Thermallyconductive substrate 802 is heated by resistance heater 810 at theupstream end of tube 820, and the thermal energy is allowed to travelalong substrate 802. This produces, when observed in a particularlocation, a heat up rate that is determined from the characteristics ofthe thermally conductive substrate. By varying the material and itscross sectional area, it was possible to control the rate of heat up.The resistive heater is embedded in substrate 802 at one end. However,it could be embedded into both ends, or in a variety of positions alongthe substrate and still allow the temperature gradient to move along thecarrier and/or substrate.

[0162] A tenth example 900 of an aerosolization device of the presentinvention will be described in reference to FIGS. 21 and 22. Air ischanneled through a fine mesh metal screen 902 on which drug isdeposited. Screen 902 is positioned across airway passage 910 (e.g.,constructed from 18 mm glass tubing). The two sides of the screen areelectrically connected to charged capacitor 920 throughsilicon-controlled rectifier (SCR) 922 to make a circuit. The charge ofthe capacitor is calculated and set at a value such that, when actuator930 closes SCR 922, the energy from capacitor 920 is converted to adesired temperature rise in screen 902.

[0163] General Considerations

[0164] The device of the present invention utilizes a flow of gas (e.g.,air) across the surface of a compound (60) to sweep away vaporizedmolecules. This process drives vaporization as opposed to condensationand therefore enables aerosol formation at relatively moderatetemperatures. Nicotine (1 mg, bp 247° C./745 mm), for example, vaporizedin less than 2 s at about 130° C. in a device of the present invention.Similarly, fentanyl (bp>300° C./760 mm) was vaporized around 190° C. inquantities up to 2 mg.

[0165] Purity of an aerosol produced using a device of the presentinvention is enhanced by limiting the time at which a compound (60) isexposed to elevated temperatures. This is accomplished by rapidlyheating a thin film of the compound to vaporize it. The vapors are thenimmediately cooled upon entry into a carrier gas stream.

[0166] Typically, compound 60 is subjected to a temperature rise of atleast 1,000° C./second. In certain cases, the compound is subjected to atemperature rise of at least 2,000° C./second, 5,000° C./second, 7,500°C. or 10,000° C./second. A rapid temperature rise within the compound isfacilitated when it is coated as a thin film (e.g., less than 10μ, 5μ,4μ, 3μ, 2μ, or 1μ in thickness). The compound is oftentimes coated as afilm between 10μ and 10 mm, 5μ and 10 mm, 4μ and 10 mm, 3μ and 10 mm, 2μand 10 mm, or even 1μ to 10 nm in thickness.

[0167] Rapid temperature rises and thin coatings ensure that compoundsare substantially vaporized in a short time. Typically, greater than 0.1mg, 0.25 mg, 0.5 mg, 0.75 mg or 1 mg of a compound is vaporized in lessthan 100 milliseconds from the start of heating. Oftentimes, the sameamount of compound is vaporized in less than 75 milliseconds, 50milliseconds, 25 milliseconds, or 10 milliseconds from the start ofheating.

[0168] Examples of compounds that have benefited from rapid heating in adevice of the present invention include lipophilic substance #87 andfentanyl. Lipophilic substance #87 decomposed by more than 90% whenheated at 425° C. for 5 minutes, but only 20% when the temperature waslowered to 350° C. Decomposition of the substance was further lowered toabout 12% when the heating time was decreased to 30 seconds and to lessthan 2% at 10-50 milliseconds. A fentanyl sample decomposed entirelywhen heated to 200° C. for 30 seconds, and only 15-30% decomposed whenheated for 10 milliseconds. Vaporizing fentanyl in device 1 led to lessthan 0.1% decomposition.

[0169]FIG. 23 is a plot of theoretical data calculated from amathematical model. See “Aerosol Technology” W. C. Hinds, second edition1999, Wiley, New York. It shows the time in seconds it takes for thenumber concentration of an aerosol to aggregate to half of its originalvalue as a function of the particle concentration. For example, a 1.0 mgvaporized dose of a compound with a molecular weight of 200 that ismixed into 1 liter of aire will have approximately 3×10¹⁸ molecules(particles)-in the liter. This results in a number concentration of3×10¹⁵/cc. Extrapolating from FIG. 23, one can see that it takes lessthan 10 milliseconds for the number of particles to halve in thisexample. Therefore, to insure uniform mixing of a vaporized compound,the mixing must occur in a very short time. FIG. 23 also shows that whenthe number concentration of the mixture reaches approximately 10⁹particles/cc, the particle size is “stable” for the purpose of drugdelivery by inhalation.

[0170]FIG. 23 is for an aerosol having a Coagulation Coefficient (K) of5×10⁻¹⁶ meters³/second. This K value corresponds to a particle size of200 nm. As the particle size changes, so can its K value. Table 1 belowgives the K values for various particle sizes. As K increases, the timerequired for the aerosol to aggregate from a particular particle size toa larger particle size is reduced. As can be seen from Table 1 and FIG.24, when the particle is in the 10 nm to 100 nm range, the effect of achanging K value tends to accelerate the coagulation process towards 100nm in size. TABLE 1 Coagulation Coefficient (× e⁻¹⁵ Particle size(diameter in nm) meters³/second) 1 3.11 5 6.93 10 9.48 20 11.50 50 9.92100 7.17 200 5.09 500 3.76 1000 3.35 2000 3.15 5000 3.04 10000 3.00

[0171] In creating an aerosol of a particular particle size, the ratioof mass of vaporized compound to the volume of the mixing gas is thecontrolling condition. By changing this ratio, the particle size can bemanipulated (see FIG. 29). However, not all compounds and not all gases,with the same ratio will result in the same particle size distribution(PSD). Other factors must be known to be able to accurately predict theresultant particle size. A compound's density, polarity, and temperatureare examples of some of these factors. Additionally, whether thecompound is hydrophilic or hydrophobic will affect the eventual particlesize, because this factor affects an aerosol's tendency to grow bytaking on water from the surrounding environment.

[0172] In order to simplify the approach used to predict the resultingparticle size, the following assumptions were made:

[0173] 1. The compound is non polar (or has a weak polarity).

[0174] 2. The compound is hydrophobic or hydrophilic with a mixing gasthat is dry.

[0175] 3. The resultant aerosol is at or close to standard temperatureand pressure.

[0176] 4. The coagulation coefficient is constant over the particle sizerange and therefore the number concentration that predicts the stabilityof the particle size is constant.

[0177] Consequently, the following variables are taken intoconsideration in predicting the resulting particle size:

[0178] 1. The amount (in grams) of compound vaporized.

[0179] 2. The volume of gas (in cc's) that the vaporized compound ismixed into.

[0180] 3. The “stable” number concentration in number of particles/cc.

[0181] 4. The geometric standard deviation (GSD) of the aerosol.

[0182] Where the GSD is 1, all of the particle sizes are the same sizeand therefore the calculation of particle size becomes a matter ofdividing a compound's mass into the number of particles given by thenumber concentration and from there calculating the particle sizediameter using the density of the compound. The problem becomesdifferent, though, if the GSD is other than 1. As an aerosol changesfrom a GSD of 1 to a GSD of 1.35, the mass median diameter (MMD) willincrease. MMD is the point of equilibrium where an equal mass ofmaterial exists in smaller diameter particles as exists in largerdiameter particles. Since total mass is not changing as the GSD changes,and since there are large and small particles, the MMD must becomelarger as the GSD increases because the mass of a particle goes up asthe cube of its diameter. Therefore larger particles, in effect, carrymore weight and the MMD becomes larger to “balance” out the masses.

[0183] To determine the effect of a changing GSD, one can start with theformula for the mass per unit volume of an aerosol given a known MMD,GSD, density, and number concentration. The formula is from Finlay's“The Mechanics of Inhaled Pharmaceutical Aerosols” (2001, Academicpress). Formula 2.39 states that the mass per unit volume of an aerosolis:

M=(ρNπ/6)(MMD)³ exp[−9/2(lnσ_(g))²]

[0184] Where:

[0185] ρ=density in gm/cc

[0186] N=Number concentration in particles/cc

[0187] MMD=mass median diameter (in cm)

[0188] σ_(g)=the GSD

[0189] M=the mass per unit volume of the aerosol in gms/cc

[0190] If the change in the MMD is considered as an aerosol changes fromone GSD to another, while the density, number concentration, and themass remain unchanged the following equality can be set up:

ρNπ/6(MMD ₁)³ exp[−9/2(lnσ_(g1))² ]=ρNπ/6(MMD ₂)³ exp[−9/2(lnσ_(g2))²]

[0191] simplifying:

(MMD ₁)³ exp[−9/2(lnσ_(g1))²]=(MMD ₂)³ exp[−9/2(lnσ_(g2))²]

[0192] Or

(MMD ₁)³/(MMD ₂)³ =exp[−9/2(lnσ_(g2))² ]/exp[−9/2(lnσ_(g1))²]

[0193] If one sets the GSD of case 1 to 1.0 then:

exp[−9/2(lnσ_(g1))²=1

[0194] And therefore:

(MMD ₁ /MMD ₂)³ =exp[−9/2(lnσ_(g2))²]

[0195] Or:

MMD ₁ /MMD ₂ =exp[−3/2(lnσ_(g2))²]

[0196] It is advantageous to calculate the change in the MMD as the GSDchanges. Solving for MMD₂ as a function of MMD₁ and the new GSD₂ yields:

MMD ₂ =MMD ₁ /exp[−3/2(lnσ_(g2))²] for a σ_(g1)=1

[0197] To calculate MMD₁, divide the compound's mass into the number ofparticles and then, calculate its diameter using the density of thecompound.

MMD ₁=(6C/ρNV)^(1/3) for an aerosol with a GSD of 1

[0198] Where:

[0199] C=the mass of the compound in gm's

[0200] ρ=Density in gm/cc (as before)

[0201] N=Number concentration in particles /cc (as before)

[0202] V=volume of the mixing gas in cc

[0203] Insertion of MMD₁ into the above equation leads to:

MMD ₂=(6C/ρNVπ)^(1/3) /[exp[−3/2(lnσ_(g2))²], measured in centimeters.

[0204] A resultant MMD can be calculated from the number concentration,the mass of the compound, the compound density, the volume of the mixinggas, and the GSD of the aerosol.

[0205] The required vaporization rate depends on the particle size onewishes to create. If the particle size is in the 10 nm to 100 nm range,then the compound, once vaporized, must be mixed, in most cases, intothe largest possible volume of air. This volume of air is determinedfrom lung physiology and can be assumed to have a reasonable upper limitof 2 liters. If the volume of air is limited to below 2 liters (e.g.,500 cc), too large a particle will result unless the dose is exceedinglysmall (e.g., less than 50 μg).

[0206] In the 10 nm to 100 mm range, doses of 1-2 mg are possible. Ifthis dose is mixed into 2 liters of air, which will be inhaled in 1-2seconds, the required, desired vaporization rate is in the range ofabout 0.5 to about 2 mg/second.

[0207] The first example of the present invention is shown in FIG. 1 andis the basic device through which the principles cited above have beendemonstrated in the laboratory. This device is described in detail inthe EXAMPLES.

[0208] In the second example of the present invention shown in FIG. 9,the use of a reduced airway cross section increases the speed of the airacross the compound's surface to about 10 meters/second. If completemixing is to happen within 1 millisecond, then the distance the gas andvaporized mixture must travel to achieve complete mixing must be nolonger than 10 millimeters. However, it is more desirable for completemixing to happen before the compound has aggregated to a larger size, soa desirable mixing distance is typically about 1 millimeter or less.

[0209] In the fourth example of the present invention shown in FIGS.10-13, an aerosol having particles with an MMAD in the 10 nm to 100 nmrange is generated by allowing air to sweep over a thin film of thecompound during the heating process. This allows the compound to becomevaporized at a lower temperature due to the lowering of the partialpressure of the compound near the surface of the film.

[0210] The fifth example shown in FIG. 14, the sixth example shown inFIGS. 15 and 16, and the eighth example shown in FIG. 19 overcome aproblem with certain compounds that react rapidly with oxygen atelevated temperatures. To solve this problem, the compound is heated inan expandable container (fourth example), a small container housingunder a vacuum or containing a small amount, e.g., about 1 to about 10ml, of an inert gas (fifth example). Once a compound is vaporized andmixed with an inert gas while the gaseous mixture is maintained at atemperature sufficient to keep the compound in its vaporized state, thegaseous mixture is then injected into an air stream. The volume of inertgas can also be re-circulated over the surface of the heated compound toaid in its vaporization as shown in FIG. 16. In the seventh example, thecompound is introduced into the gas as a pure vapor. This involvesvaporizing the compound in an oven or other container and then injectingthe vapor into an air or other gas stream through one or more mixingnozzles.

[0211] In the sixth example shown in FIGS. 17-18, gas is passed througha first tube and over discrete substrate particles, having a largesurface area to mass ratio, and coated with the compound. The particlesare heated as shown in FIG. 17 to vaporize the compound, or the gas isheated and the heated gas vaporizes the compound as shown in FIG. 18.The gaseous mixture from the first tube is combined with the gas passingthrough second tube to rapidly cool the mixture before administering itto a patient.

[0212] The eighth example shown in FIG. 20 is a thermal gradient devicethat is similar to device 1 used in the laboratory experiments. Thisexample also has a moving heating zone without any moving parts,accomplished by establishing a heat gradient that transverses from oneend of the device to the other over time. As the heating zone moves,exposed portions of the compound are sequentially heated and vaporized.In this manner the vaporized compound can be introduced into a gasstream over time.

[0213] The ninth example shown in FIGS. 21-22 is the screen device andis preferred for generating a aerosols containing particles with an MMADgreater than 100 nm. In this example, air is channeled through a finemesh screen upon which the drug to be administered to the patient hasbeen deposited.

[0214] The examples above can create aerosols without significant drugdecomposition. This is accomplished while maintaining a requiredvaporization rate for particle size control by employing a shortduration heating cycle. An airflow over the surface of the compound isestablished such that when the compound is heated and reaches thetemperature where vaporization is first possible, the resulting compoundvapors will immediately cool in the air. In the preferred examples, thisis accomplished by extending the increased velocity and mixing regionover an area that is larger than the heating zone region. As a result,precise control of temperature is not necessary since the compoundvaporizes the instant its vaporization temperature is reached.Additionally because mixing is also present at the point ofvaporization, cooling is accomplished quickly upon vaporization.

[0215] Application of the present invention to human inhalation drugdelivery must accommodate constraints of the human body and breathingphysiology. Many studies of particle deposition in the lung have beenconducted in the fields of public health, environmental toxicology andradiation safety. Most of the models and the in vivo data collected fromthose studies, relate to the exposure of people to aerosolshomogeneously distributed in the air that they breathe, where thesubject does nothing actively to minimize or maximize particledeposition in the lung. The International Commission On RadiologicalProtection (ICRP) models are examples of this. (See James AC, StahlhofenW, Rudolph G, Egan M J, Nixon W, Gehr P, Briant J K, The respiratorytract deposition model proposed by the ICRP Task Group, RadiationProtection Dosimetry, 1991; vol. 38: pgs.157-168).

[0216] However, in the field of aerosol drug delivery, a patient isdirected to breathe in a way that maximizes deposition of the drug inthe lung. This kind of breathing usually involves a full exhalation,followed by a deep inhalation sometimes at a prescribed inhalation flowrate range, e.g., about 10 to about 150 liters/minute, followed by abreath hold of several seconds. In addition, ideally, the aerosol is notuniformly distributed in the air being inhaled, but is loaded into theearly part of the breath as a bolus of aerosol, followed by a volume ofclean air so that the aerosol is drawn into the alveoli and flushed outof the conductive airways, bronchi and trachea by the volume of cleanair that follows. A typical deep adult human breath has a volume ofabout 2 to 5 liters. In order to ensure consistent delivery in the wholepopulation of adult patients, delivery of the drug bolus should becompleted in the first 1-1½ liters or so of inhaled air.

[0217] As a result of the constraints of human inhalation drug delivery,a compound should be vaporized in a minimum amount of time, preferablyno greater than 1 to 2 seconds. As discussed earlier, it is alsoadvantageous, to keep the temperature of vaporization at a minimum. Inorder for a compound to be vaporized in 2 seconds or less and for thetemperature to be kept at a minimum, rapid air movement, in the range ofabout 10 to about 120 liters/minute, should flow across the surface ofthe compound.

[0218] The following parameters are optimal in using a device of thepresent invention, due to human lung physiology, the physics of particlegrowth, and the physical chemistry of the desirable compounds:

[0219] (1) The compound should to be vaporized over approximately 1 to 2seconds for creation of particles in the ultra fine range.

[0220] (2) The compound should to be raised to the vaporizationtemperature as rapidly as possible.

[0221] (3) The compound, once vaporized, should be cooled as quickly aspossible.

[0222] (4) The compound should be raised to the maximum temperature fora minimum duration of time to minimize decomposition.

[0223] (5) The air or other gas should be moved rapidly across thesurface of the compound to achieve the maximum rate of vaporization.

[0224] (6) The heating of the air or other gas should be kept to aminimum, i.e., an increase of temperature of no greater than about 15°C. above ambient.

[0225] (7) The compound should be mixed into the air or other gas at aconsistent

[0226] (8) As the gas speed increases across the compound beingvaporized, the cross sectional area through the device should decrease.Furthermore, as the surface area of the compound increases the heatingof the gas increases.

[0227] The parameters of the design for one of the examples shown inFIGS. 2-5, 7 and 8 are the result of meeting and balancing the competingrequirements listed above. One especially important requirement for anaerosol containing particles with an MMAD between 10 nm and 100 nm isthat a compound, while needing to be vaporized within at least a1-second period, also needs to have each portion of the compound exposedto a heat-up period that is as brief as possible. In this example, thecompound is deposited onto a foil substrate and an alternating magneticfield is swept along a foil substrate heating the substrate such thatthe compound is vaporized sequentially over no more than about a onesecond period of time. Because of the sweeping action of the magneticfield, each segment of the compound has a heat-up time that is much lessthan one second.

[0228] In the example noted directly above, the compound is laid down ona thin metallic foil. In one of the examples set forth below, stainlesssteel (alloy of 302, 304, or 316) was used in which the surface wastreated to produce a rough texture. Other foil materials can be used,but it is important that the surface and texture of the material is suchthat it is “wetted” by the compound when the compound is in its liquidphase, otherwise it is possible for the liquid compound to “ball” upwhich would defeat the design of the device and significantly change thevolatilizing parameters. If the liquid compound “balls” up, the compoundcan be blown into and picked up by the airflow without ever vaporizing.This leads to delivery of a particle size that is uncontrolled andundesirable.

[0229] Stainless steel has advantages over materials like aluminumbecause it has a lower thermal conductivity value, without anappreciable increase in thermal mass. Low thermal conductivity ishelpful because heat generated by the process needs to remain in theimmediate area of interest.

EXAMPLES

[0230] The following examples further illustrate the method and variousexamples of the present invention. These examples are for illustrativepurposes and are not meant to limit the scope of the claims in any way.

Example 1 In vivo Results Using Example 1

[0231] In this example, example 1, was designed to deliver anexperimental dose of fentanyl between 20 μg and 500 μg, in a range ofultra fine particle sizes, in about 800 cc of air to a 10 kg dog. Thelung volume of each dog under experimentation was approximately 600-700cc and the device was designed to deliver the compound to the lung inthe first half of the inhalation. Because of the value of theseparameters, device 1 in this experiment can be considered a ¼ scaledevice for administering a dose to a human. It is believed that scalingthe device to work for human subjects involves mainly increasing theairflow through the device. The time frame of the introduction of thecompound into the heating/vaporization/mixing zone was set such that thecompound vaporized into a volume of air that was suitable for both thevolume required by dog lung anatomy (600-700 cc) and the volume neededto control the ratio of the compound to the air.

[0232] The following was the sequence of events that took place duringeach operation:

[0233] 1. At the beginning of the run, the operator triggered inhalationcontroller 30 to start monitoring data from pressure transducer 240 andinput flow meter 4.

[0234] 2. Controller 30 signaled controller 20 to start example 1 and tobegin collecting data from the two temperature sensors and flow meter 4.

[0235] 3. After a pre-programmed delay, example 1 initiated thegeneration of the aerosol. (Note: there was a delay of about 0.4 secondsbetween the start of the controller 30 and the start of aerosolgeneration.)

[0236] 4. After an independent preprogrammed delay (from originaltrigger signal), controller 30 opened input valve 58 to start forcedinhalation to a dog under experimentation.

[0237] 5. Example 1 completed the aerosol generation during theinhalation.

[0238] 6. Controller 30 monitored flow meter 4 and pressure transducer240 throughout the inhalation and closed off flow at input valve 58 whena pre-specified volume or pressure was met. (Note: the pre-specifiedpressure is a safety feature to prevent injury to the subject animal.Termination of the breath at the pre-specified volume is the desirableoccurrence of the experiment.)

[0239] 7. After a breath hold delay (5 seconds), exhaust valve 40 wasopened and the dog was allowed to exhale.

[0240] 8. Exhaled aerosol was trapped on exhaust filter 40 for lateranalysis. Controller 30 recorded values for the following: volumedispensed, terminal pressure, duration of air pulse, and average flowrate. Controller 20 continuously recorded at millisecond resolution,input flow rate, exhaust flow rate, foil temperature, mouthpiecetemperature, slide position, heater on/off time, and other internaldiagnostic electrical parameters.

[0241] Three weight-matched female beagle dogs received fentanyl at a100 μg intravenous bolus dose. The same dogs received fentanyl UF forInhalation (100 μg aerosolized and administered as two successiveactivations of device 1, containing approximately 50 μg fentanyl base)at a particle size of 80 nm (MMAD). The aerosol was administered toanesthetized dogs via the system schematically represented in FIG. 1,with a target delivered volume of 600-700 ml air, followed by a 5 secondbreath hold. After dosing, plasma samples for pharmacokinetic analysiswere obtained at various time points from 2 min to 24 hr. Fentanylremaining in device 1 was recovered and measured. Fentanylconcentrations were measured by using a validated GC method, with alimit of detection of 0.2 ng/ml.

[0242] Plasma pharmacokinetics from this example were compared tointravenous (IV) fentanyl (100 μg) in the same dogs. Inhalation offentanyl resulted in rapid absorption (C_(max), maximum concentration inplasma, 11.6 ng/ml and T_(max), maximum time, 2 min.) and highbioavailability (84%). The time course of inhaled fentanyl was nearlyidentical to that of IV fentanyl. Thus, fentanyl UF for inhalation hadan exposure profile that was similar to that of an IV injection.

[0243] Standard non-compartmental pharmacokinetic methods were used tocalculate pharmacokinetic parameters for each animal. The maximumconcentration in plasma (C_(max)) and the maximum time it occurred(T_(max)) were determined by examination of the data. The area under theplasma concentration vs. time curve (AUC) was determined. Thebioavailability (F) of inhaled fentanyl was determined as:

[0244] F=(DIV/DINHAL)*(AUCINHAL/AUCIV)

[0245] where D was the dose and AUC was the AUC determined to the lastmeasurable time point.

[0246]FIG. 26 plots the data obtained on the blood levels, by dog, forboth the IV doses and the inhalation doses using device 1 as describedabove under Example 1.

[0247] The fentanyl aerosol was rapidly absorbed, with the same T_(max)(2 min, the earliest time point) observed for both routes ofadministration. The maximum plasma concentration of fentanyl aerosol(11.6±1.9 ng/ml) was nearly two-thirds that of IV fentanyl (17.6±3.6ng/ml). Plasma concentrations fell below the assay limit of quantitationby 6-8 hr after IV administration and by 3-4 hr after aerosolinhalation. Bioavailability calculations were based on the AUC'sobserved to the last measurable time point for the inhalationadministration. Bioavailability for the inhalation study was 84% basedon the nominal (uncorrected) fentanyl dose.

[0248] The mean plasma elimination half-life was similar after IV (75.4min) and inhalation dose. Distribution phase half-lives (3-4 min) werealso similar after both routes of administration. The inter-animalvariability of pharmacokinetic parameters after the inhalation dose waslow, with relative standard deviations (RSD <25%) lower than thoseobserved for IV administration.

Example 2 In vitro Results Using Example 1

[0249] Table 2 below summarizes the data collected from use of example 1for in vitro testing of fentanyl. Particle size was measured with aMoudi cascade impactor. TABLE 2 Compound Mass (ug) Mixing air volume(cc) MMAD (nm) GSD 20 400  71 1.9 25 400  72-78 1.7-1.8 50 400  77-881.7-185 100 400 100-105 1.4-1.8 200 400 103-123 1.6-1.9 300 400 140-1601.8-2.1

Example 3 Use of Example 1 to Make Fine Aerosol Particles

[0250] In this example, example 1 was slightly modified and the flowrate changed, as discussed below, to make a fine aerosol in the 1 to 3micron particle size range.

[0251] Airway section 140 was removed and the air channelheating/vaporization zone 70 was changed. An airway insert (not shown)had a “roof” that was 0.25 inches above the foil. There were no mixingrods as rapid mixing was not desirable in this example. Because of thesetwo device changes, there was much less mixing with the air, thus thevapor/aerosol cloud was mixed with less air and produced a largerparticle size aerosol. The airflow rate was reduced 1 liter/minute inthis example. Again, this allowed the vapor to be mixed with much lessair, resulting in the larger particle size aerosol.

[0252] Some operational problems with high compound loading on foil 64in example 1 were encountered. The compound tested, dioctyl phthalate(DOP), was an oil and during the aerosolization process, a substantialquantity was blown downwind and not aerosolized. Three additional designalternatives were made to address this issue, involving changes to thesubstrate surface that the compound was deposited on. In the threealternatives, the substrate was made to “hold” the compound through theuse of texture They were: a) texturing the foil; b) adding a stainlesssteel screen on top of the foil; and, c) replacing the foil with a finestainless steel screen.

[0253] The results from this example are set forth below in Table 3below: TABLE 3 Substrate Type MMAD, microns GSD Emitted Dose, ugTextured foil 1.49 microns 1.9 97 Textured foil 2.70 microns 1.95 824Fine screen alone 1.59 microns 1.8 441 Fine screen alone 1.66 microns1.8 530 Screen on Foil 2.42 microns 2.2 482

[0254] As shown above, a fine particle size can be made with device 1merely by changing the ratio of the compound to the mixing air.

Example 4 In vitro Results Using Example 700

[0255] A tank was partially filled with DOP and placed inside an oven(not shown) having an inlet and an outlet. DOP was used as the testcompound. The tank was purged with helium prior to heating the tank andits contents to a temperature of 350° C. Helium was pumped through thetank and used to carry the DOP vapor out of the outlet. The gaseousmixture of helium and vaporized compound 60 was introduced intodifferent size mixing tubes through a nozzle. Each of the tubes bad airmoving through them at 14 liters/minute. The nozzle was perpendicular tothe flow direction. After this gaseous mixture was mixed with the air,the resulting aerosol was introduced into a parallel flow diffusionbattery for particle size analysis. Results are set forth in Table 4below. TABLE 4 Mixing tube size (ID) MMAD GSD   4.8 mm  65 nm 1.3 14 mm516 nm 3.3

[0256] As can be seen above, as the tube diameter became larger so didthe particle size. Additionally, as the diameter became larger, the GSDalso became larger. As the tube becomes larger, it is believed that thevaporized gas is introduced into a smaller segment of the mixing gasbecause the gas is being introduced as a point source leading to unevenmixing, which results in a large GSD.

Example 5 In vitro Results Using Example 800

[0257] To demonstrate effectiveness of example 800, a 4-inch long pieceof aluminum was fitted with a 150-watt cartridge heater at one end. Theheater was powered with a variac AC power transformer. The thickness ofthe aluminum was designed to ensure that heat would transverse from oneend of the aluminum to the other in approximately 30 seconds.

[0258] On the topside of the aluminum, an indentation was machined tohold the compound and to hold one of two top covers. The indentation forthe compound was approximately 3.5 inches long and 0.4 inches wide. Theindentation was 0.025 inches deep, and was filled with 1 mg of DOP.

[0259] The first top consisted of a sheet of flat glass placed 0.04inches above the heated surface, creating an airway. At the exit end anoutlet was fitted allowing the air to be drawn into an analyticalmeasurement device. Air was made to flow through the airway at a rate of15 liters/minute.

[0260] In the second configuration, the top was replaced with a halfcylinder made of glass. This increased the cross sectional area of theairway by an order of magnitude.

[0261] Particle size was measured with both configurations and shown tobe affected by the cross sectional area of the airway.

[0262] Results from the thermal gradient test are set forth in Table 5below: TABLE 5 Cover size and cross-section MMAD GSD Small  92 nm 1.4Big 650 nm unknown

[0263] As shown above, the results confirm that as the cross sectionbecomes larger, so does the particle size.

Example 6 In vitro Results Using Example 900

[0264] In this example for producing aerosols, airway passage 910 wasconstructed from 18 mm diameter glass tubing. However, the passage canbe made in any shape with a comparable cross-sectional area and out ofany suitable material. The screen size, mesh, and the amount of compoundwere chosen in this example so that a gas could pass through the screenwithout interference once the compound had been deposited on it.

[0265] Because the internal resistance of the screen was low, i.e.,between 0.01 and 0.2 ohms, the discharge rate (the RC time constant) ofthe capacitor was rapid, and on the order of a few milliseconds, i.e.less than 20 milliseconds, preferably in the range of about 2 to about10 milliseconds. Upon discharge of capacitor 902 and the subsequentheating of screen 902, the deposited compound was rapidly vaporized.Because air moved through screen 902, the vaporized compound rapidlymixed with air and cooled.

[0266] The compound was deposited onto the fine stainless steel screen,e.g., 200 mesh, made from 316 stainless steel, having measurements of2.54 cm.×2.54 cm. The current from the capacitor was passed between oneedge and another. It was not necessary to heat the screen totemperatures comparable to the thin foil in Example 1, because thecompound vaporized at a lower temperature due to the rapid air movement.Rapid air movement allowed the compound to vaporize at a lower vaporpressure, since airflow constantly removed compound vapors from thesurface as soon as they were formed. Thus, the compound vaporized at alower temperature without decomposition.

[0267] Deposition of the compound onto the screen was accomplished bymixing the compound with an organic solvent until the compounddissolved. The resulting solution was then applied to the fine stainlesssteel screen 902 and the solvent was allowed to evaporate. The screenwas then inserted into holder 940 that electrically connected two sidesof screen 902 to the power circuit described above.

[0268] A 10,000 mF capacitor was discharged while the gas was passingthrough screen 902. The rapid heat up of the screen resulted in a rapidvaporization of the compound into the gas. Thus the resulting vaporizedcompound was mixed into a small volume of the gas. Because the ratio ofthe mass of the compound to the volume of the mixing gas was large, afine (1-3 micron diameter) particle aerosol was made.

Example 7 Flash Device for Forming Aerosols

[0269] A high-power flashcube (GE or Sylvania), which can produce300-400 J of energy, was inserted into an anodized aluminum tube. Theflashcube/tube assembly was dipped into an organic solution containing adrug and quickly removed. Evaporation of residual solvent from theassembly was performed by placing it into a vacuum chamber for 30 min.This left a film of drug coated on the exterior surface of the aluminumtube. The flashbulb assembly was electrically connected to two 1.5 Vbatteries and a switch using copper wires and then enclosed in a sealed,glass vial. Ignition of the flashbulb was performed by momentarilyturning on the switch between the flashbulb and batteries. Afterignition, the vial was kept closed for 30 minutes such that particles ofvolatilized drug coagulated and condensed on the inside surface of thevial. Analysis of the aerosol involved rinsing the vial with 5 mL ofacetonitrile and injecting a sample of the organic solution into anHPLC.

[0270] Measurement with a fast thermocouple indicated that the aluminumtube heated up to 600° C. in 50 milliseconds. This translates into aheating rate of 12,000°/s.

[0271] One of ordinary skill in the art would understand that theexperimental device detailed above could be transformed into aninhalation delivery device by excluding the sealed vial and including ahousing to contain the assembly and electrical components. The housingwould contain an air inlet and a mouthpiece such that, when drugvolatilization occurred, an inhaled breath would carry the formedaerosol into the lungs of a subject.

Example 8 Relationship Between Film Thickness and Aerosol Purity

[0272] Sildenafil was dissolved in a minimal amount of dichloromethane.The resulting solution was coated onto a piece of pure aluminum foil,and the residual solvent was allowed to evaporate. The coated foil wasplaced on an aluminum block that had been preheated to 275° using a hotplate. A pyrex beaker was synchronously placed over the foil, and thecoated material was allowed to vaporize for 1 min. The beaker wasremoved, and the adsorbed aerosol was extracted using dichloromethane.HPLC analysis (250 nm) of an aliquot of the extract provided purity datafor the aerosol. Using this procedure the following data were obtained:3.4μ thickness, 84.8% purity; 3.3μ thickness 80.1% purity; 1.6μthickness, 89.8% purity; 0.8μ thickness, 93.8% purity; 0.78μ thickness,91.6% purity; 0.36μ thickness, 98.0% purity; 0.34μ thickness, 98.6%purity; 0.29μ thickness, 97.6% purity; and, 0.1μ, 100% purity.

Example 9 General Procedure for Screening Drugs to DetermineAerosolization Preferability

[0273] Drug (1 mg) is dissolved or suspended in a minimal amount ofsolvent (e.g., dichloromethane or methanol). The solution or suspensionis pipeted onto the middle portion of a 3 cm by 3 cm piece of aluminumfoil. The coated foil is wrapped around the end of a 1½ cm diameter vialand secured with parafilm. A hot plate is preheated to approximately300° C., and the vial is placed on it foil side down. The vial is lefton the hotplate for 10 s after volatilization or decomposition hasbegun. After removal from the hotplate, the vial is allowed to cool toroom temperature. The foil is removed, and the vial is extracted withdichloromethane followed by saturated aqueous NaHCO₃. The organic andaqueous extracts are shaken together, separated, and the organic extractis dried over Na₂SO₄. An aliquot of the organic solution is removed andinjected into a reverse-phase HPLC with detection by absorption of 225nm light. A drug is preferred for aerosolization where the purity of thedrug isolated by this method is greater than 85%. Such a drug has adecomposition index less than 0.15. The decomposition index is arrivedat by subtracting the percent purity (i.e., 0.85) from 1.

[0274] One of ordinary skill in the art can combine the foregoingembodiments or make various other embodiments and aspects of the methodand device of the present invention to adapt them to specific usages andconditions. As such, these changes and modifications are properly,equitably, and intended to be, within the full range of equivalents ofthe following claims.

1. A method of forming an aerosol for use in inhalation therapycomprising: (a) heating a substrate coated with a composition comprisinga drug at a rate greater than 1000° C./s, thereby forming a vapor; and,(b) allowing the vapor to cool, thereby forming an aerosol, which isused in inhalation therapy
 2. The method according to claim 1, whereinthe substrate is heated at a rate of about 2000° C./s.
 3. The methodaccording to claim 1, wherein greater than 0.1 mg of the composition isvaporized in less than 100 milliseconds from the start of heating. 4.The method according to claim 1, wherein the substrate is heated at arate greater than 5,000° C./s.
 5. The method according to claim 4,wherein greater than 0.25 mg of the composition is vaporized in lessthan 100 milliseconds from the start of heating.
 6. The method accordingto claim 5, wherein the substrate is heated at a rate greater than7,500° C./s.
 7. A method of forming an aerosol for use in inhalationtherapy comprising: (a) heating a substrate coated with a compositioncomprising a drug to form a vapor, wherein the coated composition is inthe form of a film less than 10μ thick; (b) allowing the vapor to cool,thereby forming an aerosol, which is used in inhalation therapy.
 8. Themethod according to claim 7, wherein the film is less than 5μ thick. 9.The method according to claim 7, wherein the film is between 5μ and 10nm thick.
 10. The method according to claim 8, wherein the film is lessthan 3μ thick.
 11. The method according to claim 9, wherein the film isbetween 3μ and 10 nm thick.
 12. A method of forming an aerosol for usein inhalation therapy comprising: (a) heating a substrate coated with acomposition comprising a drug to form a vapor in less than 100milliseconds, wherein the vapor has a mass greater than 0.1 mg; and, (b)allowing the vapor to cool, thereby forming an aerosol, which is used ininhalation therapy.
 13. The method according to claim 12, wherein thevapor has a mass greater than 0.25 mg.
 14. The method according to claim12, wherein the vapor is formed in less than 75 milliseconds.
 15. Themethod according to claim 13, wherein the vapor has a mass greater than0.5 mg.
 16. The method according to claim 14, wherein the vapor isformed in less than 50 milliseconds.